INCLUSION COMPLEXES OF BETA-CYCLODEXTRIN WITH FLURBIPROFEN, KETOPROFEN AND NAPROXEN

Abstract: The use of an NSAID of the propionic acid type- beta -cyclodextrin complex for the manufacture of a medicament for oral consumption, characterised in that the complex is administered in a solution comprising hot water. The NSAID materials are typically flurbiprofen, ketoprofen or naproxen.

Description: INCLUSION COMPLEXES OF BETA-CYCLODEXTRIN WITH FLURBIPROFEN, KETOPROFEN AND NAPROXEN This invention relates to a pharmaceutical composition containing a non- steroidal anti-inflammatory (NSAID), a process for its preparation, and a palatable formulation thereof suitable for oral consumption. In particular, the invention relates to an NSAID-cyclodextrin clathrate complex suitable for formulation in aqueous solution as a hot drink. There is a particular group of NS AIDs, known as the 'propionic acid type' which are widely indicated for the relief of pain and inflammation in disease states such as arthritis and for treatment of symptoms associated with the common cold and flu. These include for example, the drugs ibuprofen, flurbiprofen, ketoprofen and naproxen. Formulation of these drugs into a preparation suitable for oral administration, in particular into a water-soluble form suitable for liquid dosing is complicated by their poor water solubility, irritating odour and unpleasant taste. It is an object of the present invention to provide a palatable pharmaceutical composition containing an NSAID of the propionic acid type formulated for oral dosing as an aqueous solution. The ability of drug-cyclodextrin complexes to enhance water solubility and to mask unpleasant taste and odour has been known for many years. In this respect, NS AID's of the above type have proved to be very suitable candidates for complexation with cyclodextrins. Japanese patent publication, JP 56-46837 (Kowa Yakuhin Kogyo) discloses a method for the preparation of an NSAID-β-cyclodextrin clathrate complex involving the combination of ibuprofen with β-cyclodextrin in water at elevated temperature and isolation of the clathrate by spray-drying. This method is reported to yield a product containing a high percentage of ibuprofen with a molar ratio of ibuprofen to β-cyclodextrin in excess of 0.7. The increase in water solubility of the drug is considerable, being raised more than 8-fold from 10.44mg per 100ml to 89.38mg per 100ml at 27°C. The water solubility achieved by complexation with β-cyclodextrin, although significant, is not considered sufficient to permit formulation of ibuprofen as a soluble dosage form for oral administration in liquid form wherein ibuprofen is present at a therapeutic dosage level (100-600mg) in a suitable volume of water (120- 250ml). European patent publication 274 444 (Bristol Myers) describes the preparation of ibuprofen-cyclodextrin complexes using α-cyclodextrin, γ- cyclodextrin or a methylated β-cyclodextrin in place of β-cyclodextrin. The water solubility of the ibuprofen-cyclodextrin complex is further enhanced to levels of practical utility using these forms of cyclodextrin, but the high cost of these materials, reflected in the cost of medicinal products containing them, is unlikely to promote their widespread use in analgesic products, more particularly in products available for self medication for the treatment of minor aches and pains and the symtomatic relief of colds and flu. United Kingdom patent publication GB 2,219,585 (Reckitt & Colman) discloses a complex of β-cyclodextrin with the sodium, potassium, ammonium, magnesium, calcium, arginine, glycine or lysine salt of ibuprofen, having a molar ratio of ibuprofen to β-cyclodextrin in the range 1:0.2 to 1:0.75 and possessing good water solubility. These complexes are not entirely suitable for incorporation into formulations intended for oral consumption in liquid form since, on solution in water, they confer a somewhat unpleasant, soapy taste, typical of an alkaline solution. PCT application No.GB93/00702 (SmithKline Beecham pic) discloses an ibuprofen- β-cyclodextrin complex for oral consumption in a solution comprising hot water, obtainable by crystallisation from aqueous solution. It has now been found that additional propionic acid type NSAID's can be formulated with β-cyclodextrin to provide a pleasant tasting solution. Accordingly, the present invention provides further NSAID β-cyclodextrin complexes which are suitable for administration as an aqueous solution, which are palatable and yet which is relatively simple and inexpensive to manufacture in comparison with prior art compositions. Of the NSAID's of the propionic type, flurbiprofen, ketoprofen and naproxen are particularly suitable for this type of formulation. According to the present invention there is provided the use of an NSAID of the propionic acid type-β-cyclodextrin complex for the manufacture of a medicament for oral consumption as an aqueous solution, characterised in that the NSAID is flurbiprofen, ketoprofen or naproxen and the complex is administered in a solution comprising hot water. The drugs according to this invention may be as either the racemate or enantiomers. Any reference to the drug is intended to cover all active forms and may be either in the R or S enantiomer or racemate form. It has been found that a significant increase in solubility can be achieved by dosing a β-cyclodextrin complex in aqueous solution at elevated temperatures. It is therefore possible to achieve therapeutic dosage levels of the above identified NSAID's in solution in a single-dose liquid formulation. A flurbiprofen, ketoprofen or naproxen-β-cyclodextrin complex for use in the present invention can accommodate a concentration of NSAID which will deliver a single dose of up to 600mg in a volume of 200ml. Despite the known increase in solubility of many materials in water with increasing temperature, the practical reality of such a liquid 'hot remedy' is surprising. It has been reported that cyclodextrin complex stability constants decrease rapidly with increasing temperature (JACS, 101. 1864, (1979) and JCS Perkin Trans., 2, 15, (1984)). It may therefore be anticipated that dissolution in water as temperature is increased will be accompanied by a concomitant release of drug from the complex to give an undesirable oily mixture or suspension, due to the reduction in the stability constant for this type of β-cyclodextrin complex. Contrary to this expectation, it has now been found that flurbiprofen, ketoprofen or naproxen- β- cyclodextrin complexes remain homogeneous and stable in water up to a temperature of 100°C. By utilising the enhanced water solubility of flurbiprofen, ketoprofen or naproxen-β-cyclodextrin complexes at elevated temperature, there is moreover no necessity for oral administration of solutions at alkaline pH as is necessary for the cyclodextrin complexes described in GB 2, 219, 585. According to the present invention, flurbiprofen, ketoprofen or naproxen-β-cyclodextrin complexes may be administered as pleasant tasting solutions in the pH range 2.5 to 7.0. In another aspect of the invention there is provided a process for the preparation of an NSAID -β-cyclodextrin clathrate complex. These β-cyclodextrin clathrate complexes have previously been prepared by several methods including co- precipitation, freeze-drying and neutralisation precipitation methods. Each of these methods requires the use of either alkalis or organic solvents; stringent purification methods are therefore required. The spray-drying process described in JP 56-46837 avoids the use of these reagents; spray-drying is however both costly and time consuming. In contrast to the prior art processes, the process according to the present invention is both convenient and cost effective as a production method and utilises only water in addition to the NSAID and β-cyclodextrin. The process according to the invention comprises heating the NSAID and the β-cyclodextrin in water to form a solution, suitably to a temperature of 100°C, followed by crystallisation of the NSAID- β-cyclodextrin complex from the solution thus formed, suitably by maintaining the solution in the temperature range -5 to 20°C. Flurbiprofen, ketoprofen or naproxen-β-cyclodextrin complexes with a drug to β-cyclodextrin molar ratio in the range 1:1 to 1:10 are obtainable according to the process of the invention. A β-cyclodextrin complex with flurbiprofen, ketoprofen or naproxen obtainable by the process of crystallisation from aqueous solution forms an aspect of the present invention. Whilst flurbiprofen, ketoprofen or naproxen-β-cyclodextrin clathrate complexes prepared by known art methods may be utilised in formulations of the invention, a flurbiprofen, ketoprofen or naproxen-β-cyclodextrin complex obtainable by the process of crystallisation from aqueous solution is preferred for use in a liquid formulation for oral administration as hereinbefore described. A complex of the invention may be formulated in any convenient form, for example as a tablet for solution, or alternatively in powder or granular form for reconstitution with water. Accordingly, the invention provides a pharmaceutical composition comprising a β-cyclodextrin complex obtainable by crystallisation from aqueous solution in admixture with a pharmaceutically acceptable carrier. Use of a β- cyclodextrin complex as prepared by the process of the invention is not limited to oral administration in aqueous solution at elevated temperature. Complexes of the invention may be formulated for oral administration in any convenient form, for example as a swallow or chewable tablet, or as a liquid suspension. A complex obtainable by crystallisation from aqueous solution may be formulated with any appropriate carrier or adjuvant appropriate to the chosen dosage form. Thus, compositions of the invention may include for example preservatives, suspending agents, flavouring agents, bulking agents, binders, adhesives, lubricants, disintegrants, colouring agents, sweetening agents, adsorbents, thickeners and diluents, appropriate to their form. Compositions of the invention containing a β-cyclodextrin complex with flurbiprofen, ketoprofen or naproxen may in addition include other pharmaceutical agents suitable for administration therewith, including for example other analgesics, antiinflammatories and antipyretics and also expectorants, antihistamines, decongestants and antitussive agents, such as for example phenypropanolamine, phenylephrine, pseudoephedrine, dextromethorphan, caffeine, codeine and ascorbic acid. The following Examples are illustrative of the invention. In the Examples, unless otherwise stated, the abbreviation βCD refers to β- cyclodextrin undecahydrate (β-cyclodextrin. I IH2O). Example 1 - Preparation of BCD/Flurbiprofen Clathrate (1:1) BCD (4.56 g, 3.42 mmoles) was dissolved in water (75 ml) at 100°C. Flurbiprofen (0.84 g, 3.42 mmoles) was added and the resulting solution was cooled to 1°C to give a white precipitate which was isolated by filtration and dried at 50°C in a convection oven. The product, a white powder, was sieved through a 500 μm screen to yield 4.24 g of BCD/flurbiprofen clathrate, containing about 18% flurbiprofen (50 mg flurbiprofen per 284 mg of clathrate). Example 2 - Preparation of Pharmaceutical Composition containing FIurbiprofen/βCD Clathrate for Recυnstitution with Hot Water The following ingredients were sieved through a 500 μm screen and mixed together to give a homogeneous white powder: Flurbiprofen/βCD Clathrate (Example 1) 284 mg Sucrose 1876 mg Sodium Citrate 430 mg Citric Acid 680 mg Saccharin Sodium 40 mg Lemon Flavour 60 mg Sodium Cyclamate 60 mg The resulting powder was dissolved in 150 ml of hot water to give a clear, pleasant tasting solution containing 50 mg flurbiprofen per 150 ml of water. Example 2A - Preparation of Pharmaceutical Composition containing Flurbiprofen for Reconstitution with Hot Water The following ingredients were mixed together to give a homogeneous white powder: Flurbiprofen 50 mg Sucrose 1876 mg Sodium Citrate 430 mg Citric Acid 680 mg Saccharin Sodium 40 mg Lemon Flavour 60 mg Sodium Cyclamate 60 mg The resulting powder was added to 150 ml of hot water to give a suspension in which some of the drug remained undissolved. Example 3 - Preparation of Pharmaceutical Composition containing Flurbiprofen/βCD Clathrate for Reconstitution with Hot Water The following ingredients were sieved through a 500 μm screen and mixed together to give a homogeneous white powder: Flurbiprofen/BCD clathrate (Example 1 ) 568 mg Sucrose 1876 mg Sodium Citrate 430 mg Citric Acid 680 mg Saccharin Sodium 40 mg Lemon Flavour 60 mg Sodium Cyclamate 60 mg The resulting powder was dissolved in 150 ml of hot water to give a clear, pleasant tasting solution containing 100 mg flurbiprofen per 150 ml of water. Example 4 - Preparation of βCD/Ketoprofen Clathrate (5:1) BCD (53.3 g, 40 mmoles) and ketoprofen (2.03 g, 8 mmoles) were mixed with 200 ml water at 96-100°C. After stirring for 5 minutes, the resulting solution was cooled to 1 °C. The resulting suspension was filtered and the precipitate was dried for 16 hours at 50°C in a convection oven . The resulting white powder was sieved through a 500 μm screen, yielding 46.8 g of BCD/ketoprofen clathrate, containing about 3.8% ketoprofen (50 mg ketoprofen per 1316 mg of clathrate). Example 5 - Preparation of Pharmaceutical Composition containing Ketoprofen/βCD Clathrate for Reconstitution with Hot Water The following ingredients were mixed together to give a homogeneous white powder: Ketoprofen/BCD clathrate (Example 4) 1315 mg Sucrose 1876 mg Sodium Citrate 430 mg Citric Acid 680 mg Saccharin Sodium 40 mg Lemon Flavour 60 mg Sodium Cyclamate 60 mg The resulting powder was dissolved in 150 ml of hot water to give a pleasant tasting solution containing 50 mg ketoprofen per 150 ml of water. Example 5A - Preparation of Pharmaceutical Composition containing Ketoprofen for Reconstitution with Hot Water The following ingredients were mixed together to give a homogeneous white powder: Ketoprofen 50 mg Sucrose 1876 mg Sodium Citrate 430 mg Citric Acid 680 mg Saccharin Sodium 40 mg Lemon Flavour 60 mg Sodium Cyclamate 60 mg The resulting powder was added to 150 ml of hot water to give a suspension in which some of the drug remained undissolved. Example 6 - Preparation of Pharmaceutical Composition containing Ketoprofen/βCD Clathrate for Reconstitution with Hot Water The following ingredients were mixed together to give a homogeneous white powder: Ketoprofen/BCD clathrate (Example 4) 2629 mg Sucrose 1876 mg Sodium Citrate 430 mg Citric Acid 680 mg Saccharin Sodium 40 mg Lemon Flavour 60 mg Sodium Cyclamate 60 mg The resulting powder was dissolved in 150 ml of hot water to give a pleasant tasting solution containing 1 0 mg ketoprofen per 150 ml of water. Example 7 - Preparation of βCD/Naproxen Clathrate (3:1) BCD (146.5 g, 110 mmolesjand naproxen (8.4 g, 37 mmoles) were dissolved in water (300 ml) at 96-100°C. The resulting solution was cooled to 1°C to give a white precipitate which was isolated by filtration and dried for 16 hours at 50°C. The product, a white powder, was sieved through a 500 μm screen to yield 141.1 g of BCD/naproxen clathrate, containing about 5.9% naproxen (500 mg naproxen per 8418 mg of clathrate). Example 8 - Preparation of Pharmaceutical Composition containing Naproxen/βCD Clathrate for Reconstitution with Hot Water The following ingredients were mixed together to give a homogeneous white powder: Naproxen/BCD clathrate (Example 8) 4208 mg Sucrose 3417 mg Sodium Citrate 783 mg Citric Acid 1239 mg Saccharin Sodium 73 mg Lemon Flavour 109 mg Sodium Cyclamate 109 mg The resulting powder was dissolved in 150 ml boiling water to give a pleasant tasting solution containing 250 mg naproxen per 150 ml of water. Example 9 - Preparation of Pharmaceutical Composition containing Naproxen/βCD Clathrate for Reconstitution with Hot Water The following ingredients were mixed together to give a homogeneous white powder: Naproxen/BCD clathrate (Example 8) 8414 mg Sucrose 944 mg Sodium Citrate 216 mg Citric Acid 342 mg Saccharin Sodium 20 mg Lemon Flavour 30 mg Sodium Cyclamate 30 mg The resulting powder was dissolved in 150 ml of boiling water to give a clear, pleasant tasting solution containing 500 mg naproxen per 150 ml of water. Example 9A - Preparation of Pharmaceutical Composition containing Naproxen for Reconstitution in Hot Water The following ingredients were mixed together to give a homogeneous white powder: Naproxen 500 mg Sucrose 1195 mg Sodium Citrate 274 mg Citric Acid 430 mg Saccharin Sodium 25 mg Lemon Flavour 38 mg Sodium Cyclamate 38 mg The resulting powder was added to 150 ml of hot water to give a suspension in which some of the drug remained undissolved.

Claims: Claims 1. The use of an NSAID of the propionic acid type-β-cyclodextrin complex for the manufacture of a medicament for oral consumption, characterised in that the complex is not ibuprofen-β-cyclodextrin and is administered in a solution comprising hot water. 2. Use as claimed in cliam 1 wherein the NSAID is flurbiprofen, ketoprofen or naproxen. 3. Use as claimed in claim 1 or 2 wherein the NSAID-β-cyclodextrin complex delivers a therapeutic dosage level of 20 to 600mg NSAID in solution as a single dosage unit. 4. Use as claimed in claim 1 to 3 wherein the NSAID-β-cyclodextrin complex is administered in solution in the pH range 2.5 to 7.0. 5. A process for the preparation of an NSAID-β-cyclodextrin complex wherein the NSAID is flurbiprofen, ketoprofen or naproxen, comprising heating the NSAID and β-cyclodextrin in water to form a solution, followed by isolation of the NSAID-β -cyclodextrin complex by crystallisation. 6. An NSAID-β-cyclodextrin complex wherein the NSAID is flurbiprofen, ketoprofen or naproxen obtainable by crystallisation from aqueous solution. 7. An NSAID- β-cyclodextrin complex as claimed in claim 6 wherein the NSAID to β-cyclodextrin ratio is in the range 1:1 to 1:10. 8. An NSAID-β-cyclodextrin complex as defined in claim 6 or 7 for use in therapy. 9. A pharmaceutical composition comprising an NSAID-β-cyclodextrin complex as claimed in claim 6 or 7 and a pharmaceutically acceptable carrier. 10. A method for oral dosing of an NSAID of flurbiprofen, ketoprofen or naproxen comprising administering to a patient an NSAID-β-cyclodextrin complex in a solution comprising hot water.

Inventors: GRATTAN TIMOTHY JAMES, GRATTAN, TIMOTHY, JAMES
Applicants: GRATTAN TIMOTHY JAMES, SMITHKLINE BEECHAM PLC, GRATTAN, TIMOTHY, JAMES
Application year: 1994
Main classification: A61K47
IPC codes: A61K47